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ApoA-I mimetic peptide L-4F reduces significantly lipid deposits in Bruch’s membrane and complement activation in geriatric monkeys with age-related maculopathy

Session Details

Session Title: AMD II

Session Date/Time: Friday 12/09/2014 | 08:00-10:00

Paper Time: 08:32

Venue: Boulevard D

First Author: : M.Rudolf GERMANY

Co Author(s): :    A. Mohi   S. Grisanti   Y. Miura        

Abstract Details

Purpose:

Extracellular age-related neutral lipid deposits in the eye at the level of Bruch’s membrane are crucial to the development and progression of age-related macular degeneration. They build up a hydrophobic diffusion barrier causing oxidative stress and inflammation in the RPE and retina. We tested the ApoA-I mimetic peptide L-4F, which is a highly effective lipid acceptor, to wash out lipids from Bruch’s membrane and the subRPE space in geriatric monkeys with drusenoid maculopathy. Here we present the histological findings.

Setting:

Translational AMD Research Group, Depart. of Ophthalmology, University of Lübeck, Germany Euretina Innovation Award Winner 2011 Follow up Project Primate Center Münster, Germany

Methods:

In a proof of concept study we treated 9 geriatric macaques (age > 20 years) with age-related maculopathy with intravitreal injections of L-4F (n=7) or with a placebo (n=2). One eye per animal received 6 monthly injections with escalating dosages of the compounds (total ca. 625 µg). The second eye served as untreated intraindividual control. Routine ophthalmic examinations were performed included fundus photographs, OCT, intraocular pressure, and blood sampling. After 7 months all animals were sacrificed and eyes were immediately prepared for histology. Histochemistry were performed with Oil red O and Filipin for neutral lipids. Immunohistochemistry was performed against factors of the complement system.

Results:

All control animals demonstrated in both eyes an intense staining of Bruch’s membrane and choriocapillaris with Oil red O for neutral lipids and Filipin for esterified cholesterol. Eyes treated with L-4F showed a dramatic significant reduction of lipid deposits. Semiquantitative evaluation of Filipin fluorescence revealed a reduction of 82% in L-4F treated eyes compared to placebo treated eyes. Complement factor C5b also decreased by 64%.

Conclusions:

For the first time ever we could remove pharmacologically lipids from Bruch’s membrane and sub-RPE deposits in an advanced model of age-related maculopathy. Additionally, downstream effects of lipid deposition were also reduced as shown by the dramatic decrease of compliment activation. ApoA-I mimetic peptides are potential drug candidates to treat causally the underlying mechanisms of all forms of age-related macular degeneration.

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